This work builds upon previous training during the applicant's K99 phase that seeks to identify the specific chemical components of aerosol most likely responsible for observed health effects in humans. This work meets the needs ofthe proposed specific aims by exploring the mechanistic causes cardiovascular health effects observed during exposure to aged or fresh organic carbon aerosol in sensitive animal models and by investigating the role of combustion generated Ni-rich particles on cardiopulmonary injury in animal models. These aims fit within the broader mission of NIH by identifying biological effects associated with environmental contaminants. This research involves a series of in-vivo inhalation exposure studies using a murine model of cardiovascular disease. Over the course of this project, 6 sets of ApoE knockout mice will be exposed to a variety of combustion emissions aerosol. Diluted diesel exhaust will be used to mimic environmentally-relevant exposures near busy roadways. This project also includes the introduction of a custom-built photochemical aging chamber to chemically modify aerosol in order to simulate ambient aerosol processing. This improves the inhalation exposure paradigm by improving the environmental relevance of the exposure since most exposures are a composite of fresh emissions with those that are more aged. Prior to exposure, each mouse will be surgically implanted with radio telemetry devices for real time measurement of mouse activity, body temperature, and 2-channel electrocardiogram. Each exposure experiment is expected to occur 5 times per week, 6 hours per day, for 20 days. At the completion of the exposure, a number of biomarker endpoints will be measured. Brionchial lavage fluid will be collected and centrifuged and the supernatant will be analyzed for biochemical indicators of lung injury (total protein and LDH) and inflammatory cytokines.